The study of inorganic chemistry in the pharmaceutical field has been receiving special attention from researchers due to the clear advantages of its use over traditional medicines for the treatment of a series of pathologies.
The best-studied inorganic pharmaceutical is cisplatin, a drug which has been clinically used for the treatment of a wide range of tumors. It is believed that its action occurs by means of interaction with DNA, thus inhibiting the proliferation of tumor cells (Lippard, Science 218: 1075-1082 (1982); Rosenberg, Nature 222: 385 (1969); Cleare et al, Bioinorg. Chem. 2: 187 (1973)). This compound is efficient for the combat against various kinds of tumors and is highly cytotoxic, being also extensive to normal cells (Ebert, U., Loffler, H., Kirch, W., Pharmacology & Therapeutics, 74: (2) 207-220 1997; Spencer C. M., Goa K. L., Drugs, 50: (6) 1001-1031 DEC 1995).
Gold-based complexes have been used for the treatment of arthritis and its route of action involves the linkage to a thiol group of proteins, thus inhibiting the appearance of disulphite bridges, which may cause their denaturation.
Metal complexes of cobalt have also been already pointed out as presenting antiviral, antitumor and antimicrobial activity, besides anti-inflammatory properties.
Metal compounds which can change or link to functional sites of proteins resulting in the inactivation of its biological activities are described by the U.S. Pat. No. 5,880,149. The document discloses some palladium complexes (pertaining to the class of coordination compounds), as irreversible inhibitors of cysteine-proteases, as powerful antitumor drugs and as very efficient drugs in numerous infectious processes, in which the route of action of cysteine-proteases is involved. As an example, we mention the enzymatic inhibition caused by palladium complexes over Cathepsins B, H, J, L, N, S, T and C and over the Interleukine Converter Enzyme (ICE), constituting active drugs against Amebiasiss, Trypanosomiasis and Leishmaniosis. The U.S. patent is the latest work published on the development and routes of action of antitumor drugs, involving compounds of the chemical element palladium.
FERNANDEZ, Alberto et al: “Cyclopalladated compounds derived from a [C,N,S!] terdentate ligand: synthesis, characterization and reactivity. Crystal and molecular structure of [Pd{2-ClC6H3C(H)═NCH2CH2SMe}(Cl)] and {Pd [2-ClC6H3C(H)═NCH2CH2SMe]}2{μ, -Ph2P(CH2)4PPh2}]—CF3SO3]2”, New Journal of Chemistry, (25-1-2002), 26(1), 105-112, XP009020790-ISSN: 1144-0546, purely refers to the synthesis and reactivity of the cyclopalladated compounds containing halogens. It does not have any similarity to the application and its biological effects. Despite containing a biphosphinic ligand in bridge, as in the invention, there is a great structural difference between compound 7 reported and the structures of the application. The difference lies on the fact that the nitrogen atom linked to the palladium has a double connection [—N(SMe)═C(H)—] which is not the case of the structures mentioned in the invention. This fact, allied to the fact that the same atom of nitrogen possesses an —SMe ligand, gives these compounds another type of reactivity, among which, the possibility of formation of tridentate complexes involving (C, N, S).
VILA, Jose M. et al: “Novel Cyclopalladated ferrocenyl Schiff base compounds with bridging and chelating diphosphines. Crystal and molecular structure of [{Pd(eta5-C5H5) Fe (eta5-C5H3)C(H):N-2,4,6-Me3C6H2]}-{Ph2P(CH2)nPPh2-P,P}][PF6](n=1,2)” Journal of Organometallic Chemistry (3-12-2001), 637-639, 577-585 XP004323943-ISSN: 0022-328X, like the previous one, it has a fundamental structural difference in relation to the invention compounds. The researcher considers Shiff Bases as metallation agents on the palladium. That gives a double connection to the nitrogen linked to the metal, as in the CpFe(C6H4)—C═NR—Pd cycle. In the invention, the requested metallation agent does not have this characteristic. In the case of ionic compounds the invention does not mention the PF6− ion.
CASTRO-JUIZ, Samuel et al: “Directed regioselectivity in cyclometallated palladium (II) compounds of N-Benzylidenebenzylamines. Crystal and molecular structure of [Pd{3,4-(OCH2O)C6H2C(H)=NCH2— [3,4-(OCH2O)C6H13]C2,N}(μ-O2CMe))2”, Polyhedron (15-11-2001), 20(24-25), 2925-2933, XP 002261131-ISSN: 0277-5387, and also in the case of N-Benzylidenebenzylamines, that contain an atom of nitrogen with double connection, and are used here as a metallation agent, there is the fundamental difference of structures of the patent document, where Y clearly represents an atom of the group V or VI of the periodic table, where the double connection is absent. The patent application shows the potential use of the palladacycle compounds as antitumoral agents since they inhibit, mainly, the cathepsin-B enzyme, which the inventors have discovered. None of this was reported by this document.
ANANIAS, Sandra R. et al: “Cleavage of the dimeric cyclopalladated [Pd(N,C-dmba) (μ-X)]2, (dmba=N,N-dimethylbenzylamine; X=SCN and NCO) by diphosphines. Palladium (II) compounds with distinct structures in the solid-state and in solution”, Transition Metal Chemistry (Dordrecht, Netherlands), (2001), 26(4,5), 570-573, XP009020786-ISSN: 0340-4285; this work of pure synthesis and palladacycle reactivity containing pseudo-halides and the metallation agent N,N-dimethylbenzylamine. Although it also involves the 1,1′ bis(difenilfosfina)ferroceno ligand in structures similar to the invention, the ligand used does not have a chiral carbon atom like in the case of the ligand that the invention has used, i.e., the N,N-dimethil-1-phenethylamine, the main compound protected in the document. Also, this document does not mention any biological effect resulting from the action of this compound on enzyme inhibition, which results in their action as antitumoral agents, the main scope of the present invention.
LOUSAME, Mariela et al: “Synthesis and single-crystal X-ray diffraction studies of new cyclometallated phenylimidazole palladium (II) compounds”, European Journal of Inorganic Chemistry, (9-2000), (9), 2055-2062 XP002261132-ISSN: 1434-1948, where the author uses phenylimidazole as a cyclomettalation agent. Also, this ligand, like the N-Benzylidenebenzylamines, contains an atom of nitrogen with double connection, which is different from the invention compounds. Therefore, there is a fundamental difference in the structures reported in the invention, where Y clearly represents an atom of the V or VI group of the periodic table, where the double connection is absent. The patent application shows the potential use of the palladacycle compounds as antitumoral agents since they inhibit, mainly, the cathepsin-B enzyme. None of this was reported by the document.
MA, Jian-Fang et al: “Reaction of di-μ-dichloro-bis(N,N-dimethylbenzylamine-C2,N) dipalladium (II) with diphosphines. Six-member ring complexes bearing Spiro rings”, Inorgânica Chimica Acta (15-3-2000), 299(2), 164-171, XP002261133-ISSN: 0020-1693; work of pure synthesis and cyclopalladated reactivity containing halides and the metallation agent N,N-dimetilbenzilamina. Although it also involves the 1,1′ bis(difenilfosfina)ferroceno ligand in structures similar to the invention, t, the ligand used does not have a carbon quiral like the ligand that the invention has used, i.e., the N,N-dimetil-1-fenetilamina, main compound protected in the document. Also, this document does not mention any biological effect resulting from the action of this compound on the inhibition of enzymes, which results in their action as antitumoral agents, the main scope of the present invention
BOEHM, Andreas et al: “Metal complexes of biologically important ligands. Part 104. Ortho-palladated complexes of N,N-dimethyl(phenyl)glicine methyl esther. Synthesis of .alpha.-amino acid derivatives by insertion of isocyanides, CO, alkenes, and alkynes into the Pd—C bond” Zeitschrift Fuer Naturforschung, B:, Chemical Sciences, (1998), 53(4), 448-458 XP009020783 ISSN: 0932-0776, wich does not have any similarity to the invention or its biological effects. Work of pure synthesis and reactivity of palladacycle containing halides and N,N-dimethilbenzylamine metallation agent. Although it also involves the 1,1′ bis(difenilfosfina)ferroceno ligand in structures similar to the invention, the ligand used does not have a chiral carbon like the ligand used by us, i.e., the N,N-dimetil-1-fenetilamina, main compound protected in the document. The document does not mention any biological effect resulting from the action of this compound on the inhibition of enzymes either, which results in their action as antitumoral agents, the main scope of the present invention.
ZHAO, Gang et al: “Optically active cyclopalladated derivatives of arylimines. Crystal structure of (+)-[{Pd[p-MeOC6H3CH═NCH2-(1S,2R,5S)—CHCH2CH2CHC(Me)2CHCH2](μ-X)}2 (X═Cl or Br), (+)-[Pd{p-MeOC6H3CH═NCH2-(1S,2R,5S)-CHCH2—CH2CHC(Me)2CHCH2}Cl(PPh3)] and (+)-[{Pd{p-MeO C6H3CH═NCH2-(1S,2R5S)—CHCH2CH2CHC(Me)2CHCH2]Cl}2-{Fe(eta-5H4PPh2)2]}” Journal of the Chemical Society, Dalton Transactions: Inorganic Chemistry (1998), (7), 1241-1247 XP-002261134-ISSN: 1472-7773; is also restricted to the synthesis and structural characterization of palladacycle compounds with optical isomeric with the biphosphinic ligand identical to the invention, i.e., the 1,1′-bis(diphenylphosphine)ferrocene. Besides, it must be pointed out once more that it uses a cyclometallation agent that, like the N-Benzylidenebenzylamines and the phenylimidazole previously mentioned, contains an atom of nitrogen with double connection, different from the invention compounds. Thus, there is a fundamental difference between the structures, where Y clearly represents an atom of the V or VI group of the periodic table, where the double connection is absent. The present invention shows the potential use of the palladacycle compounds as antitumoral agents since they inhibit, mainly, the cathepsin-B enzyme, which the inventors have discovered. None of this was reported by this document.
ZHAO, Gang et al: “Diastereoselective Cyclopalladation of New Chiral Ferrocenylimines (−)-[(eta5-C5H5) Fe {eta5-C5H4C(R)═NCH2-(1S,2R,5S)-CHCH2CH2CHC(CH3)2CHCH2}]. Crystal structures of (Sp-[Pd{(eta5-C5H3C(R)═NCH2-(1S,2R,5S)—CHCH2CH2CHC(CH3)2CHCH2)Fe(eta5-C5H5)}(PPh3)Cl] (R═H or Me)” Organometallics (2-7-1997), 16(18), 4023-4026 XP002261135-ISSN: 0276-7333, which is also restricted to the synthesis and structural characterization of palladacycle compounds with optical isomery with the biphosphinic ligand identical to the invention, i.e., the 1,1′-bis(diphenylphosphine) ferrocene. Furthermore, it must be stressed that this document uses a cyclometallation agent that, like the N-Benzylidenebenzylamines and the phenylimidazole previously mentioned, contains an atom of nitrogen with double connection, different from the invention compounds. Thus, there is a fundamental difference in the structures presented in the patent document, where Y clearly represents an atom of the group V or VI of the periodic table, where the double connection is absent. The present invention shows the potential use of the palladacycle compounds as antitumoral agents since they inhibit, mainly, the cathepsin-B enzyme, which the inventors have discovered. None of this was reported by the document.
QUIROGA, A. G. et al: “Novel tetranuclear orthometalated complexes of Pd (II) and Pt (II) derived from p-iospropylbenzaldehyde thiosemicarbazone with cytostatic activity in cis-DDP resistant tumor line cells. Interaction of these complexes with DNA”, Journal of Medicinal Chemistry, (23-4-1998), 41(9), 1399-1408, XP002261136-ISSN: 0022-2623, shows the obtainment of tetranuclear palladacycle compounds with a structure quite different from those mentioned in the invention. It also shows the antitumoral activity of those compounds. The patent, however, is very clear regarding the need of a ligand ferrocenyl-phosphines or similar in the structure. It also claims antitumoral action for the invention compounds since they have properties that operate as enzymatic inhibitors and modulators of the immunological system, which is totally novel, according to claims 1-93 of the present invention.
NAVARRO-RANNINGER, C. et al: “Cyclometalated complexes of platinum and palladium with N-(4-chlorophenyl)-alpha-benzoylbenzylideneamine. In vitro cytostatic activity, DNA modification and interstrand cross-link studies” Inorganic Chemistry (28-8-1996), 35(18), 5181-7 XP002261137-ISSN: 0020-1669, which describes the synthesis and structural characterization of cyclopalladated compounds with antitumoral activity, approaching its interaction with DNA molecules. However, it does not mention ferrocenyl-phosphine ligands and similar ones, which are the object of the invention. It does not mention enzymatic inhibition mechanisms either.
NAVARRO-RANNINGER, C. et al: “Analysis of two chloroplatinated compounds derived from N-(4-methoxyphenyl)-alpha-benzoylbenzylidenamide: Comparison of the activity of these compounds with other isostructural cyclopalladated compounds” Journal of Medicinal Chemistry (26-11-1993), 36(24), 3795-3801 XP002261138-ISSN: 0022-2623 which describes the synthesis and structural characterization of cyclopalladated with antitumoral activity, approaching its interaction with DNA molecules. However, it does not mention ferrocenyl-phosphine ligands and similar ones, which are the object of the invention. It does not mention any enzymatic inhibition mechanisms either.